Project Summary/Abstract The long-term goal of our laboratory is to characterize the structure and function of the acute phase protein, C-reactive protein (CRP) and to relate these findings to human autoimmune diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibodies against nuclear antigens. The etiology of SLE is incompletely understood, but there is a strong genetic component. One genetic risk factor is related to polymorphisms in the promoter for CRP. Low levels of CRP expression are associated with increased risk of developing SLE and lupus nephritis. Our studies demonstrated that CRP suppresses disease in mouse models of SLE and other immune complex (IC) diseases. The mechanism by which CRP protects from SLE remains unknown. Our data from several inflammatory models show that the interaction of CRP with Fcg receptors (FcgR) on macrophages induces a regulatory phenotype. We hypothesize that this regulatory macrophage suppresses IC-mediated inflammation and initiates long-term immunoregulation in SLE. Specific Aim 1 is to examine the induction of suppressive macrophages by CRP and determine their phenotype. We have produced suppressive macrophages by treating spleen cells, splenic macrophages or bone marrow macrophages (BMM) with CRP. We will examine the phenotype of these macrophages with respect to cytokine and chemokine production and cell surface markers. We will determine the requirements for induction of this phenotype. We will also determine the localization and persistence of transferred suppressive macrophages. Specific Aim 2 is to define the role of macrophages in CRP suppression of autoimmune disease in mouse models of SLE. The goal of this Aim is to determine how this suppression is initiated. We will test the ability of CRP-treated macrophages to transfer suppression of disease activity in the MRL/lpr model. We will use macrophage depletion to determine whether macrophages are required for CRP suppression of SLE. Specific Aim 3 is to examine the role of Treg induction in the long-term suppression of disease. We will determine whether direct CRP treatment or transfer of CRP-treated macrophages or spleen cells leads to the generation of increased numbers and activity of Treg in SLE mice. We will examine the ability of CRP and CRP- treated cells to alter the numbers or distribution of Treg in nonautoimmune mice using FoxP3egfp mice under inflammatory and non-inflammatory conditions. These studies will provide insight into the mechanisms by which CRP initiates and maintains suppression of autoimmune and inflammatory disease. The studies described are directly related to treatment of a common autoimmune disease, SLE, which is an important Veterans health problem. A patent based on the use of CRP for treatment of autoimmune nephritis has been issued by the US patent office. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Relevance to Veterans Health. SLE is an autoimmune disease that primarily affects younger women who represent a significant proportion of our active military, reserve and Veteran populations. Disease incidence is 3.5-fold higher among African-Americans than Americans of European descent. SLE remains an incurable disease with devastating consequences for many patients despite increasingly effective treatments. Genetic factors play an important role in the development of this disease. One of the most recently identified genetic risk factors is the regulation of CRP synthesis. Therefore, understanding the role this protein plays in the risk for SLE will aid in understanding the cause and treatment of this and other autoimmune diseases in Veterans.